Recent Advances in Catalytic Enantioselective Construction of Monofluoromethyl-Substituted Stereocenters

Abstract

Chiral organofluorine compounds featuring a monofluoromethyl (CH₂F)-substituted stereocenter are often encountered in a number of drugs and bioactive molecules. Consequently, the development of catalytic asymmetric methods for the enantioselective construction of CH₂F-substituted stereocenters has received great progress over the past two decades, and a variety of enantioselective transformations have been accordingly established. According to the kinds of fluorinated reagents or substrates employed, these protocols can be divided into the following major categories: i) enantioselective ring opening of epoxides or azetidinium salts by fluoride anion; ii) asymmetric monofluoromethylation with 1-fluorobis(phenylsulfonyl)methane; iii) asymmetric fluorocyclization of functionalized alkenes with Selectfluor; iv) asymmetric transformations involving α-CH₂F ketones, α-CH₂F alkenes, or other CH₂F-containing substrates. This feature article aims to summarize these recent advances, discuss the possible reaction mechanisms, advantages and limitations of each protocol and their applications. The synthetic opportunities still open for further development are illustrated as well. This review article would inspire for the researchers engaged in asymmetric catalysis, organofluorine chemistry, and medicinal chemistry.